Action Points

Note that this post-hoc analysis of a randomized, controlled trial demonstrated no association between digoxin treatment and mortality in patients with atrial fibrillation.

Be aware that these data contradict other analyses of the same trial that used different methodologies.

Digoxin is not associated with increased risk of death or hospitalization in atrial fibrillation, a post-hoc analysis of the AFFIRM trial found, but the results contradict another post-hoc study published just 5 months ago.

During a 3.4-year follow-up, there was no difference in all-cause death among propensity matched patients on digoxin therapy and those not on the drug (14% and 13%, respectively), according to Ali Ahmed, MD, of the University of Alabama at Birmingham, and colleagues.

Those taking digoxin also did not have an increase in hospitalization or rate of incident nonfatal arrhythmias, the researchers wrote online in the European Heart Journal.

These findings contradict the November 2012 post-hoc analysis of AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) by Claude S. Elayi, MD, of the Gill Heart Institute at the University of Kentucky in Lexington, and colleagues who found a 41% increased risk of death in patients taking digoxin (adjusted hazard ratio 1.41, 95% CI 1.19 to 1.67).

An earlier post-hoc analysis of the trial by the AFFIRM investigators also found a higher risk of all-cause death associated with digoxin (HR 1.42, 95 CI 1.09 to 1.86), according to their study in Circulation (2004; 109: 1509–1513).

Ahmed and colleagues addressed both studies, saying those researchers used a statistical approach called "time-varying treatment" where patients who continued to receive digoxin over 3.4 years of the follow-up to AFFIRM were compared with those who did not.

If patients continued digoxin treatment over the long term because they had heart failure, it may inadvertently attribute higher mortality to digoxin when it may actually be due to heart failure, they said.

Ahmed and colleagues found that nearly three-quarters of AFFIRM patients with heart failure at the start of the trial were receiving digoxin, suggesting that heart failure was a reason for digoxin use in those patients.

"When we accounted for how many patients in the digoxin group had heart failure going in, the association between digoxin and mortality disappeared," Ahmed told MedPage Today.

"The approach of the other two studies are valid as long as the treatment is not for a condition that has higher morbidity and mortality. Otherwise, you will conclude misleadingly that digoxin was the cause of the mortality when it was not," he said.

Elayi told MedPage Today that bias is inherent in all post-hoc analyses. "If we really want to provide an answer, we will need to conduct a randomized trial, where one group of patients has digoxin and the other one will not have digoxin. However, we don't have such a trial. That's why we consider data from other trials."

He said it's important to consider all the evidence and pointed to an observational study presented at the recent American College of Cardiology meeting that showed a higher risk of death associated with digoxin (9.49 versus 4.27 per 100 person-years), but no difference in the rate of hospitalization, at a median follow-up of 0.8 years.

In the original AFFIRM trial, 4,060 patients with paroxysmal and persistent atrial fibrillation were randomized to receive rate-control or rhythm-control strategies. Follow-up was up to 6 years and researchers found no significant difference between the strategies. However, in older patients, the rate-control group had a lower mortality.

"There are very few drugs effective for rate control and digoxin is one of them. The reason it is a second-line therapy for younger patients is because it is less efficient in controlling the heart rate when you're active," Ahmed said.

"But for older, less active patients, digoxin is as equally recommended as beta-blockers and calcium channel blockers, and probably more so because many patients cannot tolerate the side effects such as hypotension associated with calcium channel blockers and depression and confusion associated with beta-blockers," he added.

Digoxin was one of the four rate-control drugs used in the AFFIRM trial, the other three being beta-blockers and the two non-dihydropyridine calcium channel blockers, verapamil, and diltiazem.

Ahmed and colleagues used a propensity score matching model to overcome the biases they did not like in previous studies. Matched patients had a mean age of 70, 40% were women, and 11% were nonwhite.

They found that digoxin was not associated with significant risk of all-cause death at 1, 2, 3, and 12 months follow-up, nor was it significantly associated with mortality when used as monotherapy or in combination with other rate-controlled drugs.

In adjusted models and in multivariate analyses, digoxin had no association with all-cause hospitalization.

"These findings are consistent with those of the main AFFIRM trial in which patients in the rate-control group had a trend towards lower mortality," they wrote.

"Considering that digoxin is remarkably free of side effects, when used appropriately, it may be an attractive choice for patients with Afib, especially among those who have other relative contraindications to drugs like beta-blockers and calcium channel blockers," they concluded.

The study was limited because the association of digoxin with outcomes was not pre-specified in AFFIRM. Also, results may not be generalizable to patients different from this subgroup analysis. There also were no data on adherence, crossover during follow-up, or digoxin dosage.

The original AFFIRM study was supported by the NHLBI. However, the current work was not supported by any grant funding and does not necessarily reflect the opinions or views of the AFFIRM study or the NHLBI.

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